Project Summary. Nongonococcal urethritis (NGU) is the most common sexually transmitted disease syndrome seen in men in the United States, yet up to 50% of cases have no defined etiology. Even less is known about the etiology of persistent or recurrent urethritis, which is also frequent. Ureaplasma urealyticum may be responsible for some of these idiopathic cases, but evidence regarding pathogencity of the organism and the degree to which it is associated with acute or persistent NGU is conflicting. Similar to the serovars of Chlamydia trachomatis, Ureaplasma serovars may exhibit varying degrees of pathogenicity, and recent phylogenetic analyses have demonstrated that the two major Ureaplasma biovar groupings are actually distinct species. U. parvum has been designated biovar 1, while the name U. urealyticum was retained for biovar 2. Limited data suggest that U. urealyticum (biovar 2), but not U. parvum is associated with NGU, but further studies are required to confirm this observation, as well as to assess the differential response of these two species to common antibiotic treatment regimens for NGU, and to identify the role of this organism in persistent or recurrent NGU. To address these questions, we will conduct a series of studies in conjunction with an ongoing randomized treatment trial of another genital Mycoplasma, M. genitalium. Specifically, we will 1) Assess the association of U. urealyticum (biovar 2) and U. parvum with acute NGU;2) Determine, in our ongoing randomized double-blind trial, the relative efficacy of azithromycin and doxycycline in eradicating U. urealyticum (biovar 2) and U. parvum infection among men with NGU, and assess the relationship of the MIC of the drug used to persistence of U. urealyticum (biovar 2) and U. parvum;and 3) Evaluate the association of persistent or recurrent NGU with U. urealyticum (biovar 2) and U. parvum. Relevance. NGU is the subject of over 200,000 physician office visits per year (CDC, 2001), and represents a significant public health problem. The results of this study may lead to the identification of an additional cause of this syndrome, provide guidance on treatment decisions, and shed light on the etiology of persistent and recurrent cases.